Epigenetic mechanisms have been proposed to underlie the transition from drug use to abuse by modifying key brain reward circuitry, both functionally and structurally. Accumulating evidence has described a role for the class IIa histone deacetylases (HDACs) as key epigenetic regulators in this process. This class contains four members (HDAC4, 5, 7 and 9) and is unique in its ability to shuttle in and out of the nucleus. We have reported that the localization of the class IIa HDAC, HDAC5 is regulated by cocaine. Furthermore, nuclear accumulation of HDAC5 results in an attenuation of cocaine reward. When in the nucleus class IIa HDACs act to limit transcriptional processes and may thus result in modifications of cellular function and structure. Importantly, the only well characterized target of HDAC5 in the nucleus is the transcription factor myocyte enhancer factor 2 (MEF2) which has been characterized as a negative regulator of spine density. Taken together, these findings suggest a potential role for HDAC5 in modulating functional plasticity that results in behavioral adaptations to cocaine as well as in the regulation of spine formation. Therefore, this proposal aims to test the regulation and role of nuclear accumulation of HDAC5 in a rodent model of addiction, self- administration. To this end aim 1 is designed to test the hypothesis that localization of HDAC5 is regulated in vivo by cocaine self-administration. Aim 2 proposes to use viral-mediated overexpression of wild type HDAC5 or a nuclear form of HDAC5 in order to assess its contribution in the development of an addicted-like phenotype. Finally, aim 3 will test a potential role for HDAC5 in regulation of spine density by using viral- mediated overexpression of wildtype HDAC5 or a nuclear form of HDAC5 during chronic cocaine self- administration followed by diolistics, immunohistochemistry and spine analysis using confocal microscopy.